Cyclohepta[b][1,4]diazepino[6,7,1,-hi]indoles and derivatives

ABSTRACT

This invention provides compounds of the formula: 
                         
wherein R 1  and R 2  are each, independently, H, alkyl, cycloalkyl, —CH 2 -cycloalkyl, alkoxy, halogen, fluorinated alkyl, —CN, —NH—SO 2 -alkyl, —SO 2 —NH-alkyl, alkyl amide, amino, alkylamino, dialkylamino, fluorinated alkoxy, acyl, or phenoyl or thiophenoyl; R 3  and R 4  are each, independently, H, alkyl or cycloalkyl; R 5  is H or alkyl; R 6  is H or; and the dashed line indicates an optional double bond; or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions and methods utilizing these compounds for the treatment or prevention of disorders including obsessive-compulsive disorder, depression, anxiety, generalized anxiety disorder, schizophrenia, migraine, sleep disorders, eating disorders, obesity, epilepsy, and spinal cord injury.

This application is a continuation of application Ser. No. 10/016,743,filed Nov. 2, 2001, now U.S. Pat. No. 6,858,604 which claims the benefitunder 35 U.S.C. §119(e) of provisional Application No. 60/245,598, filedNov. 3, 2000, the entire disclosure of which is hereby incorporated byreference.

The present invention relates tocyclohepta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives thereof,which are serotonin 5-hydroxytryptamine 2_(C) (5HT_(2C)) receptoragonists useful for the treatment or prevention of disorders includingobsessive-compulsive disorder, depression, anxiety, generalized anxietydisorder, schizophrenia, migraine, sleep disorders, eating disorders,obesity, epilepsy, and spinal cord injury.

BACKGROUND OF THE INVENTION

Obesity is a medical disorder characterized by an excess of body fat oradipose tissue. Comorbidities associated with obesity are Type IIdiabetes, cardiovascular disease, hypertension, hyperlipidemia, stroke,osteoarthritis, sleep apnea, gall bladder disease, gout, some cancers,some infertility, and early mortality. As the percentage of obeseindividuals continues to rise both in the U.S. and abroad, obesity isexpected to be a major health risk in the 21^(st) Century. The serotonin5-hydroxytryptamine (5-HT) receptor is a G-protein coupled receptorwhich is expressed in neurons in many regions of the human centralnervous system. [Wilkinson, L. O. and Dourish, C. T. in SerotoninReceptor Subtypes: Basic and Clinical Aspects (ed. Peroutka, S. J.)147-210 (Wiley-Liss, New York, 1991).] The 5HT_(2C) receptor (formerlycalled the 5HT_(1C) receptor) is a prominent subtype of the serotoninreceptor found in the central nervous system of both rats and humans. Itis expressed widely in both cortical and subcortical regions. [Julius,D. MacDermott, A. B., Axel, R. Jessell, T. M. Science 241:558-564(1988).] Studies in several animal species and in humans have shown thatthe non-selective 5HT_(2C) receptor agonist, meta-chlorophenylpiperazine(MCPP) decreases food intake. [Cowen, P. J., Clifford, E. M. , Williams,C., Walsh, A. E. S., Fairburn, C. G. Nature 376: 557 (1995).] Tecott, etal have demonstrated that transgenic mice lacking the 5HT_(2C) receptoreat more and are heavier than Wild Type mice. [Tecott, L. H., Sun, L.M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Daliman, M. F.,Jullus, D. Nature 374: 542-546 (1995).] Compounds of this invention are5HT_(2C) receptor subtype selective agonists which are selective overother monoamine receptors, causes a reduction in food intake and resultin a reduction in weight gain. Other therapeutic indications for5HT_(2C) agonists are obsessive compulsive disorder, depression, panicdisorder, schizophrenia, sleep disorders, eating disorders, epilepsy,and spinal cord injury.

U.S. Pat. No. 3,914,250 (Oct. 21, 1975) describes1,4-diazepino[6,5,4-jk]carbazoles as anticonvulsant agents. Thecompounds of this invention are not carbazoles. This invention relatesto cyclohepta[b][1,4]diazepino[6,7,1-hi]indoles and derivatives whichbind to and activate 5HT_(2C) receptors in the CNS and are useful forthe treatment of CNS disorders which can benefit from modulation of the5HT_(2C) receptor.

DESCRIPTION OF THE INVENTION

This invention provides compounds of formula I having the structure

wherein:

-   R₁ and R₂ are each, independently, hydrogen, alkyl of 1-6 carbon    atoms, cycloalkyl of 3 to 7 carbon atoms, —CH₂-cycloalkyl of 3 to 7    carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkyl    of 1 to 6 carbon atoms, —CN, —NH—SO₂-alkyl of 1-6 carbon atoms,    —SO₂—NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms,    amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon    atoms per alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl    of 2-7 carbon atoms, or phenoyl or thiophenoyl;-   R₃ and R₄ are each, independently, hydrogen, C₁-C₆ alkyl or    cycloalkyl of 3 to 7 carbon atoms;-   R₅ is hydrogen or C₁-C₆ alkyl;-   R₆ is hydrogen or C₁-C₆ alkyl; and-   wherein the dashed line indicates an optional double bond;-   or a pharmaceutically acceptable salt thereof,

In the definitions of R₁ and R₂ herein, the fluorinated alkyl andfluorinated alkoxy groups indicate the specified alkyl or alkoxy groupshaving any amount of fluorine substitution, including, but not limitedto, groups such as —CHF₂, —CF₃, —C₂F₅, —OCF₃, etc.

One group of compounds of this invention are those having formula 1,above, in which R₁, R₂, R₅ and R₆ are each hydrogen and R₃ and R₄, areas defined above, or a pharmaceutically acceptable salt thereof. Anothergroup of compounds of this invention are those in which R₅ is hydrogenand R₁, R₂, R₃, R₄ and R₆ are as defined above. In another group ofcompounds of this invention, R₅, R₂ and R₃ are hydrogen and R₁, R₄ andR₆ are as defined above.

The 5HT_(2C) receptor agonists of this invention are useful for thetreatment or prevention in mammals, preferably in humans, of disordersinvolving the central nervous system such as obsessive-compulsivedisorder, depression, atypical depression, bipolar disorders, anxiety,generalized anxiety disorder, schizophrenia, psychoses, personalitydisorders, organic mental disorders, behavioral disorders associatedwith dementia or age-related conditions, aggressivity, drug and alcoholaddiction, social phobias, sexual dysfunction, panic disorder, migraine,sleep disorders, such as sleep apnea, eating disorders, such ashyperphagia, bulimia or anorexia nervosa, obesity, epilepsy, andpremenstrual tension.

This invention also includes methods of utilizing the compounds hereinin treatments or preventitive regimens for treatment of central nervoussystem deficiencies associated with trauma, stroke, neurodegenerativediseases or toxic or infective CNS disorders including, but not limitedto, encephalitis or menengitis; or cardiovascular disorders, includingthrombosis; gastrointestinal disorders such as malfunction ofgastrointestinal motility; and diabetes insipidus. These methods includethe improvement or inhibition of further degradation of central nervoussystem activity during or following the malady or trauma in question.Included in these improvements are maintenance or improvement in motorand motility skills, control, coordination and strength.

The compounds of this invention contain asymmetric carbon atoms and thusgive rise to optical isomers and diastereoisomers. While shown withoutrespect to stereochemistry in Formula I, the present invention includessuch optical isomers and diastereoisomers; as well as the racemic andresolved, enantiomerically pure R and S stereoisomers; as well as othermixtures of the R and S stereoisomers and pharmaceutically acceptablesalts thereof.

The term “alkyl” includes both straight- and branched-chain saturatedaliphatic hydrocarbon groups and cycloalkyl groups. Halogen is Cl, Br,F, or I.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids.

Preferred compounds of this invention are those in which R is hydrogen.Especially preferred are compounds, which are enantiomerically purestereoisomers of compounds where R is hydrogen and the indole ring isreduced or not reduced.

The compounds of this invention can be prepared according to thefollowing scheme from commercially available starting materials orstarting materials, which can be prepared using literature procedures.Scheme 1 shows the preparation of a key intermediate and Scheme 2 showsthe preparation of representative compounds of this invention.

According to Scheme I, a substituted or unsubstituted isatoic anhydrideis allowed to react with substituted or unsubstituted glycinehydrochloride or an ester of the same in an organic base such aspyridine or triethylamine, to give either open-chain intermediate I orthe benzodiazepinedione II. Intermediate I can be converted tointermediate II by heating in the presence of an acid, such as aceticacid. The benzodiazepinedione II is reduced to the benzodiazepine IIIusing a reducing agent such as lithium aluminum hydride or aborane-tetrahydrofuran complex. The secondary nitrogen atom in III isprotected using a protecting group, such as an amide by reacting IIIwith an acylating agent, such as acetic anhydride, in the presence of abase, such as triethylamine, to give an acylated benzodiazepine IV.

According to Scheme 2, Intermediate IV is allowed to react with anitrosating agent, such as sodium nitrite, in the presence of an acid,such as acetic acid, to give nitroso compounds V. The nitroso compoundsare reduced to hydrazines VI using a reducing agent, such as zinc powderin acetic acid and water. The hydrazines VI are allowed to react withsubstituted or unsubstituted cycloheptanones in acid, such as aceticacid, to give the fused indoles VII. The fused indoles VII can betreated with a base, such as NaOH, in a polar solvent, such as water oran alcohol, or with an acid, such as hydrochloric acid, to give thefused indoles VIII, which are products of this invention. In addition,fused indoles VII can be reduced, with a reducing agent, such as sodiumcyanoborohydride, in the presence of an acid, such as acetic acid, togive fused indolines IX which are products of this invention. Fusedindolines IX are diastereoisomeric mixtures that can be resolved usingchiral HPLC or chiral resolving agents to give stereo isomers X and XIand enantiomers thereof, which are products of this invention. Also,compounds VII can be reduced with reducing agents, such as a borane-THFcomplex, to give XII which are compounds of this invention.

The acylation steps of this invention are understood to includereactions of the appropriate compound with any acylating agent andreaction conditions known in the art. Useful in these steps areacylating agents include acid halides and esters or anhyrides of theappropriate aliphatic carboxylic acid. Useful acid halides includeacetyl chloride, propionyl chloride, isobutyryl chloride, benzoylchloride, etc. Acid anhydrides include acetic anhydride and benzoicanhydride. Similarly, alkylation steps herein are understood to includeany relevant alkylating agents and conditions known in the art. Theseinclude, but are not limited to the use of alkyl halides, such as methyliodide, or alkyl tosylates or aldehyde alkylating agents in the presenceof an applicable reducing agent.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known pharmaceutically acceptable acids.The processes herein will be understood to include an optionaladditional step of forming a salt form of the products via standardaddition reactions with any pharmaceutically acceptable organic orinorganic acid.

The ability of the compounds of this invention to act as 5HT_(2C)agonists was demonstrated in several standard pharmacological testprocedures; the procedures used and results obtained are provided below.

Test Procedures

5HT_(2C) Receptor Binding Test Procedure

To evaluate high affinity for the 5HT2_(C) receptor, a CHO (ChineseHamster Ovary) cell line transfected with the cDNA expressing the human5-hydroxytryptamine2_(C) (h5HT2_(C)) receptor was maintained in DMEM(Dulbecco's Modified Eagle Media) supplied with fetal calf serum,glutamine, and the markers: guaninephosphoribosyl transferase (GTP) andhypoxanthinethymidine (HT). The cells were allowed to grow to confluencein large culture dishes with intermediate changes of media andsplitting. Upon reaching confluence, the cells were harvested byscraping. The harvested cells were suspended in half volume of freshphysiological phosphate buffered saline (PBS) solution and centrifugedat low speed (900×g). This operation was repeated once more. Thecollected cells were then homogenized with a polytron at setting #7 for15 sec in ten volumes of 50 mM Tris.HCl, pH 7.4 and 0.5 mM EDTA. Thehomogenate was centrifuged at 900×g for 15 min to remove nuclearparticles and other cell debris. The pellet was discarded and thesupernatant fluid recentrifuged at 40,000×g for 30 min. The resultingpellet was resuspended in a small volume of Tris.HCl buffer and thetissue protein content was determined in aliquots of 10-25 microliter(μ1) volumes. Bovine Serum Albumin (BSA) was used as the standard in theprotein determination by the method of Lowry et al., (J. Biol. Chem.,193:265 (1951). The volume of the suspended cell membranes was adjustedwith 50 mM Tris.HCl buffer containing: 0.1% ascorbic acid, 10 mMpargyline and 4 mM CaCl₂ to give a tissue protein concentration of 1-2mg per ml of suspension. The preparation membrane suspension (many timesconcentrated) was aliquoted in 1 ml volumes and stored at −70 C untilused in subsequent binding experiments.

Binding measurements were performed in a 96 well microtiter plateformat, in a total volume of 200 μl. To each well was added: 60 μl ofincubation buffer made in 50 mM Tris.HCl buffer, pH 7.4 and containing 4mM CaCl₂; 20 μl of [¹²⁵I] DOI (S.A., 2200 Ci/mmol, NEN Life Science).

The dissociation constant, KD of [¹²⁵I] DOI at the human serotonin5HT_(2C) receptor was 0.4 nM by saturation binding with increasingconcentrations of [¹²⁵I] DOI. The reaction was initiated by the finaladdition of 100.0 μl of tissue suspension containing 50 μg of receptorprotein. Nonspecific binding is measured in the presence of 1 μMunlabeled DOI added in 20.0 μl volume. Test compounds were added in 20.0ml. The mixture was incubated at room temperature for 60 min. Theincubation was stopped by rapid filtration. The bound ligand-receptorcomplex was filtered off on a 96 well unifilter with a Packard®Filtermate 196 Harvester. The bound complex caught on the filter diskwas dried in a vacuum oven heated to 60° C. and the radioactivitymeasured by liquid scintillation with 40 μl Microscint-20 scintillant ina Packard TopCount® equipped with six (6) photomultiplier detectors.

Specific binding is defined as the total radioactivity bound less theamount bound in the presence of 1 μM unlabeled DOI. Binding in thepresence of varying concentrations of test drugs is expressed as percentof specific binding in the absence of drug. These results are thenplotted as log % bound vs log concentration of test drug. Non linearregression analysis of data points yields both the IC50 and the Kivalues of test compounds with 95% confidence limits. Alternatively, alinear regression line of decline of data points is plotted, from whichthe IC50 value can be read off the curve and the Ki value determined bysolving the following equation:

${Ki} = \frac{IC50}{1 + {L/{KD}}}$where L is the concentration of the radioactive ligand used and the KDis the dissociation constant of the ligand for the receptor, bothexpressed in nM.

The following Ki's are provided for various refrence compounds:

Ki value and 95% confidence interval.

Ritanserin  2.0 (1.3–3.1) nM Ketanserin 94.8 (70.7–127.0) nM Mianserin 2.7 (1.9–3.8) nM Clozapine 23.2 (16.0–34.0) nM Methiothepin  4.6(4.0–6.0) nM Methysergide  6.3 (4.6–8.6) nM Loxapine 33.0 (24.0–47.0) nMmCPP  6.5 (4.8–9.0) nM DOI  6.2 (4.9–8.0) nM

Stimulation of [³H] Inositol Monophosphate Production by 5-HT_(2C)Agonists.

CHO cells transfected with the cDNA expressing the human 5-HT_(2C)receptor were cultured in Dulbecco's modified Eagle's medium (DMEM)supplemented with 10% fetal bovine serum and non-essential amino acids.Upon reaching confluence the cells were harvested using PBS/EDTA andplated in 24 well plates at an initial density of 2.5×10⁵ cells perwell. One (1) ml of maintenance medium containing 1 μCi/ml myo-[³H]inositol was added to each well. After 48 hours labeling, the cells werewashed once with 0.5 ml DMEM containing 25 mM HEPES and 10 mM LiCl, thenpreincubated with the medium for 30 min (antagonists were included inthis period if tested). At the end of the preincubation, the medium wasremoved, the cells were then incubated with test compounds (in presenceof antagonists if needed) for 30 min. The reaction was terminated byremoval of the incubation solution and addition of 0.5 ml ice-cold 5%PCA, followed by 15 to 30 min incubation on ice. 200 μl of 0.5 M Tes/1.5M K₂CO₃ was added to each well to neutralize to pH 7, and plates wereleft on ice for another 15 to 30 min to precipitate all salts. Theliquid and solid phases were separated by centrifugation.

A portion (350 μl) of the upper aqueous phase was applied to DowexAG-1X8 (formate form, 100-200 mesh) columns. The columns were thenwashed stepwise with 10 ml of water and 10 ml of 25 mM ammonium formateto remove free myo-[³H]inositol and deacylated phosphoinositol,respectively. Finally 10 ml of 0.2 M ammonium formate solution wasapplied to the columns to elute [³H] inositol monophosphate ([³H] IP₁)directly into scintillation vials. Of this eluate, 1 ml was used todetermine radioactivity by scintillation counting.

Agonist-stimulated levels of [³H]inositol monophosphate (IP₁) isexpressed as a percentage of the response observed with a maximallyeffective concentration of 5-HT (10 μM). A 3-parameter logistic functionis used to generate estimate of EC₅₀/IC₅₀. Antagonists are tested in thepresence of 10 μM 5-HT.

The following data are provided for various reference compounds:

5-HT 15.1 nM EC₅₀ mCPP 46.8 nM EC₅₀ 60% E_(MAX) (relative to 5-HT)SB200646  286 nM IC₅₀ (10 μM 5-HT as agonist)Results

Results from in vitro Test Procedures 5HT_(2C) Affinity 5HT_(2C)Stimulation DOI/Agonist binding % Emax of IP3 Compound (Ki, nM) (5HT,100%) (EC50, nM) Example 1 38 73 500 Example 2

The results obtained in this standard pharmacological test proceduresdemonstrate that the compounds of this invention are 5HT_(2C) receptoragonists useful for the treatment of diseases involving the centralnervous system such as obsessive-compulsive disorder; depression;anxiety; generalized anxiety disorder, panic disorder; schizophrenia;migraine; sleep disorders, such as sleep apnea; eating disorders, suchas hyperphagia; obesity; epilepsy, and spinal cord injury.

This invention also comprises pharmaceutical compositions comprising oneor more of the compounds of this invention, or a pharmaceuticallyacceptable salt thereof, and one or more pharmaceutically acceptablecarriers or excipients. The compounds of this invention can beformulated neat or with a pharmaceutical carrier for administration, theproportion of which is determined by the solubility and chemical natureof the compound, chosen route of administration and standardpharmacological practice. The pharmaceutical carrier may be solid orliquid.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets preferably contain up to 99% of the active ingredient. Suitablesolid carriers include, for example, calcium phosphate, magnesiumstearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose,methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine,low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,lethicins, and oils (e.g. fractionated coconut oil and arachis oil). Forparenteral administration, the carrier can also be an oily ester such asethyl oleate and isopropyl myristate. Sterile liquid carriers are usefulin sterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by, for example, intramuscular,intraperitoneal or subcutaneous injection. Sterile solutions can also beadministered intravenously. The compounds of this invention can also beadministered orally either in liquid or solid composition form.

The compounds of this invention may be administered rectally orvaginally in the form of a conventional suppository. For administrationby intranasal or intrabronchial inhalation or insufflation, thecompounds of this invention may be formulated into an aqueous orpartially aqueous solution, which can then be utilized in the form of anaerosol. The compounds of this invention may also be administeredtransdermally through the use of a transdermal patch containing theactive compound and a carrier that is inert to the active compound, isnon toxic to the skin, and allows delivery of the agent for systemicabsorption into the blood stream via the skin. The carrier may take anynumber of forms such as creams and ointments, pastes, gels, andocclusive devices. The creams and ointments may be viscous liquid orsemisolid emulsions of either the oil-in-water or water-in-oil type.Pastes comprised of absorptive powders dispersed in petroleum orhydrophilic petroleum containing the active ingredient may also besuitable. A variety of occlusive devices may be used to release theactive ingredient into the blood stream such as a semipermeable membranecovering a reservoir containing the active ingredient with or without acarrier, or a matrix containing the active ingredient. Other occlusivedevices are known in the literature.

As used herein, the terms “pharmaceutically effective amount” or“therapeutically effective amount” means the total amount of each activecomponent of the pharmaceutical composition or method that is sufficientto show a meaningful patient benefit, i.e., treatment, prevention oramelioration of the cause or symptoms of the malady or condition, or anincrease in rate of treatment, prevention or amelioration of suchconditions. When applied to an individual active ingredient,administered alone, the term refers to that ingredient alone. Whenapplied to a combination, the term refers to combined amounts of theactive ingredients that result in the therapeutic effect, whetheradministered in combination, serially or simultaneously.

The dosage requirements vary with the particular compositions employed,the route of administration, the severity of the symptoms presented andthe particular subject being treated. Based on the results obtained inthe standard pharmacological test procedures, projected daily dosages ofactive compound would be 0.02 μg/kg-750 μg/kg. Treatment will generallybe initiated with small dosages less than the optimum dose of thecompound. Thereafter the dosage is increased until the optimum effectunder the circumstances is reached; precise dosages for oral,parenteral, nasal, or intrabronchial administration will be determinedby the administering physician based on experience with the individualsubject treated. Preferably, the pharmaceutical composition is in unitdosage form, e.g. as tablets or capsules. In such form, the compositionis sub-divided in unit dose containing appropriate quantities of theactive ingredient; the unit dosage forms can be packaged compositions,for example, packaged powders, vials, ampoules, pre filled syringes orsachets containing liquids. The unit dosage form can be, for example, acapsule or tablet itself, or it can be the appropriate number of anysuch compositions in package form.

The following exemplifies the preparation of compounds representative ofthis invention.

EXAMPLE 11,2,3,4,9,10,11,12-Octahydro-8H-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole

Intermediate A. 4-Acetyl-2,3,4,5-tetrahydro-1H-benzodiazepine

Acetic anhydride (0.60 mL) was added dropwise to a stirred suspension of2,3,4,5-tetrahydro-1H-benzodiazepine (950 mg, 6.4 mmol) in anhydrousether (25 mL). After refluxing for four hours, the reaction mixture wasfiltered to remove a solid. Evaporation of the filtrate gave a residuewhich was purified by chromatography on silica gel eluting with 5%methanol in ethyl acetate. Evaporation of the product fractions gave anoil. The solid removed by filtration above contained a mixture ofstarting material and product by thin layer chromatography. The solidwas partitioned between water and methylene chloride to remove salts andthe organic portion was purified on silica gel as described above.Evaporation of the product fractions gave the product as an oil. Bothproduct oils were dried under oil pump vacuum and gradually solidified.The first crop of intermediate A. (322 mg) melted at 83-85° C. (lit. mp:84-86° C. recrystallized from ether). The second crop of intermediate A(450 mg) isolated from the solid, melted at 75-79° C.

Anal. Calcd. for C₁₁H₁₄N₂O. Theory: % C, 69.44; % H, 7.42; % N, 14.73Found: % C, 69.6; % H, 7.52; % N, 14.71.

Intermediate A (450 mg, 2.36 mmol) was partially dissolved in water (3.8mL) containing conc. HCl (0.23 mL) while chilling in an ice/water bath.The ice bath was removed and a solution of NaNO₂ dissolved in water (0.4mL) was added dropwise with stirring. A color change from yelilow toyellow/brown resulted and an oil separated. The oil was extracted intomethylene chloride, dried (MgSO₄), filtered and evaporated to give anoil which was dissolved in glacial acetic acid (5.4 mL). Powered zinc(1.16 g, 17.8 mmol, 7.5 eq) was added portionwise at 25-35° C.(exotherm) and the mixture was allowed to stir an additional hour afterthe addition of zinc was complete. The reaction mixture was filteredinto a flask containing cycloheptanone (0.28 g, 2.6 mmol, 1.12 eq) andwas heated at 100° C. for 1.5 h. The acetic acid was removed byevaporation under reduced pressure and the residue was purified bycolumn chromatography on silica gel eluting with 3% methanol inmethylene chloride to give a residue. The residue was dissolved in conc.HCl (10 mL) and heated under reflux for 5 h. A precipitate formed. Thereaction mixture was cooled and filtered to collect a solid which wasrecrystallized from water to give the hydrochloride salt of the titlecompound as a tan solid, mp: 303-306° C.

Anal. Calcd. For C₁₆H₂₀N₂O.HCl.0.10 H₂O. Theory: % C, 69.98; % H, 7.67;% N, 10.10. Found: % C, 68.95; % H, 7.55; % N, 10.05.

EXAMPLE 21,2,3,4,8,9,10,11,12,12a-Decahydro-7bH-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole

The product of Example 1 (223 mg, 0.8 mmol) was dissolved in glacialacetic acid with stirring and the solution was cooled in an ice/waterbath. Solid sodium cyanoborohydride (75 mg) was added portionwise withstirring. The ice bath was removed and the reaction mixture was allowedto stir at room temperature under a nitrogen atmosphere for 3 h. Thevolatiles were removed under reduced pressure to give a colorless oilwhich was partitioned between 2.5 N NaOH and ethyl acetate. The organicphase was washed with saturated NaCl solution, then water and dried(MgSO₄). The dried solution was filtered and the filtrate was evaporatedunder reduced pressure to give a pale yellow oil (206 mg).

The oil (196 mg) was treated with a solution of KOH (412 mg) dissolvedin water (1 mL) and methanol (2 mL) and heated in an oil bath (95° C.)for 25 h. The volatiles were removed under reduced pressure to give aclear oil (120 mg). The oil was dissolved in 2-propanol and treated withan excess of ethereal HCl to give the hydrochloride salt of the titlecompound as a yellow solid (119 mg), mp: 258-263° C. (recrystallizedfrom 2-propanol).

Anal. Calcd for C₁₆H₂₂N₂.HCl.0.25 H₂O. Calcd: % C, 67.83; % H, 8.36; %N, 9.89. Found: % C, 67.81; % H, 8.01; % N, 9.50.

1. A method of treating in a mammal a condition selected from at leastone of schizophrenia, bipolar disorders, or psychosis, the methodcomprising administering to a mammal a pharmaceutically effective amountof a compound of formula I or a pharmaceutically acceptable saltthereof:

wherein: R₁ and R₂ are each, independently, hydrogen, alkyl of 1-6carbon atoms, cycloalkyl of 3 to 7 carbon atoms, —CH₂-cycloalkyl of 3 to7 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkylof 1 to 6 carbon atoms, —CN, —NH—SO₂-alkyl of 1-6 carbon atoms,—SO₂—NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms,amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atomsper alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7carbon atoms, phenoyl or thiophenoyl; R₃ and R₄ are each, independently,hydrogen, C₁-C₆ alkyl or cycloalkyl of 3 to 7 carbon atoms; R₅ ishydrogen or C₁-C₆ alkyl; R₆ is hydrogen or C₁-C₆ alkyl; and wherein thedashed line indicates an optional double bond.
 2. The method of claim 1wherein the mammal is a human.
 3. The method of claim 2 wherein R₁, R₂,R₃, R₄, R₅, and R₆ are independently selected from H or alkyl of 1-6carbon atoms, or a pharmaceutically acceptable salt thereof.
 4. Themethod of claim 2 wherein the compound administered is selected from atleast one of1,2,3,4,9,10,11,12-octahydro-8H-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole;or1,2,3,4,8,9,10,11,12,12a-decahydro-7bH-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole;or a pharmaceutically acceptable salt thereof.
 5. The method of claim 2wherein the condition is schizophrenia.
 6. A method of treating in amammal a condition selected from drug or alcohol addiction, socialphobias, panic disorder, sexual dysfunction, sleep disorders, eatingdisorders, gastrointestinal disorders, diabetes, obesity, epilepsy, orpremenstrual tension, the method comprising administering to a mammal apharmaceutically effective amount of a compound of formula I or apharmaceutically acceptable salt thereof:

wherein: R₁ and R₂ are each, independently, hydrogen, alkyl of 1-6carbon atoms, cycloalkyl of 3 to 7 carbon atoms, —CH₂-cycloalkyl of 3 to7 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkylof 1 to 6 carbon atoms, —CN, —NH—SO₂-alkyl of 1-6 carbon atoms,—SO₂—NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms,amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atomsper alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7carbon atoms, phenoyl or thiophenoyl; R₃ and R₄ are each, independently,hydrogen, C₁-C₆ alkyl or cycloalkyl of 3 to 7 carbon atoms; R₅ ishydrogen or C₁-C₆ alkyl; R₆ is hydrogen or C₁-C₆ alkyl; and wherein thedashed line indicates an optional double bond.
 7. The method of claim 6wherein the mammal is a human.
 8. The method of claim 7 wherein thecondition is selected from diabetes or obesity.
 9. The method of claim 7wherein the condition is selected from epilepsy.
 10. The method of claim7 wherein the condition is selected from sexual dysfunction.
 11. Themethod of claim 7 wherein R₁, R₂, R₃, R₄, R₅, and R₆ are independentlyselected from H or alkyl of 1-6 carbon atoms, or a pharmaceuticallyacceptable salt thereof.
 12. The method of claim 7 wherein the compoundadministered is selected from at least one of1,2,3,4,9,10,11,12-octahydro-8H-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole;or1,2,3,4,8,9,10,11,12,12a-decahydro-7bH-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole;or a pharmaceutically acceptable salt thereof.
 13. A method of treatinga mammal suffering from stroke, trauma or a spinal cord injury, themethod comprising administering to a mammal a pharmaceutically effectiveamount of a compound of formula I or a pharmaceutically acceptable saltthereof:

wherein: R₁ and R₂ are each, independently, hydrogen, alkyl of 1-6carbon atoms, cycloalkyl of 3 to 7 carbon atoms, —CH₂-cycloalkyl of 3 to7 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, fluorinated alkylof 1 to 6 carbon atoms, —CN, —NH—SO₂-alkyl of 1-6 carbon atoms,—SO₂—NH-alkyl of 1-6 carbon atoms, alkyl amide of 1-6 carbon atoms,amino, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atomsper alkyl moiety, fluorinated alkoxy of 1-6 carbon atoms, acyl of 2-7carbon atoms, phenoyl or thiophenoyl; R₃ and R₄ are each, independently,hydrogen, C₁-C₆ alkyl or cycloalkyl of 3 to 7 carbon atoms; R₅ ishydrogen or C₁-C₆ alkyl; R₆ is hydrogen or C₁-C₆ alkyl; and wherein thedashed line indicates an optional double bond.
 14. The method of claim13 wherein the mammal is a human.
 15. The method of claim 14 wherein R₁,R₂, R₃, R₄, R₅, and R₆ are independently selected from H or alkyl of 1-6carbon atoms, or a pharmaceutically acceptable salt thereof.
 16. Themethod of claim 14 wherein the compound administered is selected from atleast one of1,2,3,4,9,10,11,12-octahydro-8H-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole;or1,2,3,4,8,9,10,11,12,12a-decahydro-7bH-cyclohepta[b][1,4]diazepino[6,7,1-hi]indole;or a pharmaceutically acceptable salt thereof.